The alarming increase in the incidence/severity of diseases caused by Staphylococcus aureus in recent years, particularly those caused by community-associated and hospital-acquired methicillin resistant strains, call for novel effective antibacterial strategies. The disturbing findings that such strains produce more virulence-determining toxins, including superantigens (SAg), mandate a multipronged attack using a combination of drugs that act at different stages of staphylococcal infection. While antibacterials such as linezolid, which inhibit bacterial toxin production, are useful, bacteriostatics alone seem to be not very effective. This is attributed to two major reasons. (i) Bacteriostatics fail to completely shut down toxin production in vivo. (ii) In the clinical settings, there is almost alway a significant time delay between the onset of S. aureus infection and initiation of antibacterial therapy. During this delay, significant quantities of pathogenic exotoxins have already been produced. Unfortunately, bacteriostatics have no activity on pre-formed exotoxins. Therefore, antibodies could be administered to neutralize toxins that were produced prior to initiation of therapy as well as to inactivate the residual toxins produced in spite of antibacterial therapy. Such antibodies would act synergistically with bacteriostatics. Since SAg are one of the most pathogenic exotoxins of S. aureus, in vivo neutralization of SAg may be the preferred approach. In addition, SAg have the unique ability to robustly and non-specifically stimulate the immune system followed by induction of unresponsiveness or anergy. SAg, thus divert the immune response against the bacterium, thereby helping in bacterial immune evasion. Therefore, stimulating the innate immune system will also be beneficial during S. aureus infections. Hence, we propose a combination therapy with the bacteriostatic drug, linezolid, neutralizing antibodies to superantigens, and immunomodulatory agents that boost innate immunity to effectively control/eliminate S. aureus infections. The effectiveness of this novel approach will be tested using the robust HLA class II transgenic mouse model. Lethal pneumonia will be induced in HLA-DR3 transgenic mice with a highly pathogenic strain of S. aureus that produces large amounts of the SAg, staphylococcal enterotoxin B (SEB). To mimic the clinical scenario, treatment will be delayed in 2-hour increments after initiation of infection. Mice will be left untreated or treated with various combinations of linezolid, human-mouse chimeric neutralizing anti-SEB antibodies or isotype control antibodies and the toll-like receptor (TLR)-2 agonist, Pam2CSK4. Protection from mortality will be studied. Thus, we would have established an effective combination therapy against lethal S. aureus infection and identified the therapeutic window of the combination therapy. PUBLIC HEALTH RELEVANCE: The incidence and severity of diseases caused by antibiotic resistant strains of Staphylococcus aureus, producing highly pathogenic toxins are increasing drastically. Therefore, we propose to test the effectiveness of a new drug cocktail for the treatment of such S. aureus infections. Our cocktail would consist of an antibiotic, antibodies against a pathogenic staphylococcal toxin and a drug to stimulate immunity.